ZDHHC3-mediated SCAP S-acylation promotes cholesterol biosynthesis and tumor immune escape in hepatocellular carcinoma.

IF 7.5 1区生物学 Q1 CELL BIOLOGY

Cell reports Pub Date : 2024-11-09 DOI:10.1016/j.celrep.2024.114962

Mingzhi Wu, Xiaojun Zhou, Xinyi Zhou, Genxin Wang, Yiqun Zeng, Jun Li, Edward V Prochownik, Fubing Wang, Youjun Li

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引用次数: 0

Abstract

Cholesterol metabolism reprogramming plays essential roles in hepatocellular carcinoma (HCC). However, precisely how cholesterol metabolism is dysregulated is not clear. Here, we show that the palmitoyltransferase ZDHHC3 and depalmitoylase ABHD17A regulate HCC cell cholesterol biosynthesis by dynamically S-acylating SREBP cleavage-activating protein (SCAP). SCAP S-acylation by ZDHHC3 at C264 antagonizes HACE1-mediated SCAP ubiquitination. Intriguingly, SREBP2 transcriptionally upregulates ZDHHC3 to form a positive feedback loop, which explains why negative feedback regulation of SCAP/SREBP2 signaling fails in HCC. Increased cholesterol in the tumor microenvironment (TME) restrains CD4⁺ T cell cytotoxicity. Hence, the cholesterol metabolism reprogramming and cholesterol level alternation in the TME cooperate to promote HCC development. We identified a small-molecule inhibitor of ZDHHC3 that, combined with anti-PD-1 immunotherapy, inhibited diethyl nitrosamine (DEN)/CCl₄-induced HCC growth in mice. ZDHHC3-mediated SCAP S-acylation reprograms cholesterol metabolism and promotes HCC immune escape. ZDHHC3 is thus identified as a rational chemotherapy target for HCC.

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ZDHHC3 介导的 SCAP S-acylation 促进肝细胞癌中胆固醇的生物合成和肿瘤免疫逃逸。

胆固醇代谢重编程在肝细胞癌（HCC）中起着至关重要的作用。然而，胆固醇代谢是如何失调的尚不清楚。在这里，我们发现棕榈酰基转移酶 ZDHHC3 和去棕榈酰基酶 ABHD17A 通过动态 S-酰化 SREBP 裂解激活蛋白（SCAP）来调控 HCC 细胞的胆固醇生物合成。ZDHHC3在C264处对SCAP进行S-酰化可拮抗HACE1介导的SCAP泛素化。耐人寻味的是，SREBP2转录上调ZDHHC3形成正反馈回路，这就解释了为什么在HCC中SCAP/SREBP2信号传导的负反馈调节失效。肿瘤微环境（TME）中胆固醇的增加会抑制 CD4+ T 细胞的细胞毒性。因此，胆固醇代谢重编程和肿瘤微环境中胆固醇水平的变化共同促进了 HCC 的发展。我们发现了一种ZDHHC3小分子抑制剂，该抑制剂与抗PD-1免疫疗法相结合，可抑制二乙基亚硝胺（DEN）/CCl4诱导的小鼠HCC生长。ZDHHC3 介导的 SCAP S-acylation 重编程胆固醇代谢并促进 HCC 免疫逃逸。因此，ZDHHC3 被确定为治疗 HCC 的合理化疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell reports CELL BIOLOGY-

CiteScore

13.80

自引率

1.10%

发文量

1305

审稿时长

77 days

期刊介绍： Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted. The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership. The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.